When a blood vessel is damaged and the normal endothelial-cell barrier is disrupted, platelets are quickly recruited from the circulating blood to form an occlusive plug. This occurs through a series of interactions between the platelets and macromolecules in the subendothelial matrix (platelet adhesion) and among the platelets themselves (platelet aggregation). The initial process of adhesion, in contrast to aggregation, does not require metabolic activity. It leads, however, to the activation of platelets which in turn secrete a number of factors which stimulate the activation of plasma coagulation factors, resulting in the generation of a fibrin clot that reinforces the platelet aggregate. Under normal hemostatic condition the platelet aggregate and fibrin clot are degraded as healing of the injured area occurs.
Thrombosis is a pathological process in which a platelet aggregate and/or fibrin clot occlude a blood vessel. Venous thrombosis and pulmonary embolism are among the leading causes of morbidity and death in hospitalized patients. Studies with radioactively labeled fibrinogen reveal venous thrombi in the lower legs of about one fourth of all patients older than 50 years who have undergone routine inguinal herniorrhaphy, in more than one half of all prostatectomy or hip surgery patients, and in about one third of all patients with acute myocardial infarction. Predisposing factors include posttraumatic and postoperative immobility (particularly in middle-aged and elderly patients and after cardiovascular procedures), pregnancy, previous episodes of venous thrombosis, use of oral contraceptives, stroke, neoplasia, obesity, systemic lupus erythematosus, nephrotic syndrome, polycythemia vera, inflammatory bowel disease, homocystinuria, hyperhomocysteinemia, paroxysmal nocturnal hemoglobinuria, shock, and congestive heart failure.
Thrombosis that develops as a purely intravascular process may also be the primary factor in atherosclerosis. The formation of platelet aggregates on the surface of atheromatous plaques and subsequent organization of these white thrombi into fibrous occlusive intimal lesions in undoubtedly one mechanism by which atherosclerotic lesions progress to severe obstruction and total occlusion; coronary artery thrombosis leading to myocardial infarction almost always occurs at the site of an atheromatous plaque. Percutaneous transluminal coronary angioplasty (PTCA) has become an important procedure to re-establish blood flow to the heart through partially occluded blood vessels. Unfortunately approximately 30% to 40% of patients that have coronary angioplasty suffer restenosis of the treated vessel within 6 months of treatment; currently there is no reliable method of preventing vascular restenosis. A revascularization procedure such as bypass surgery or another PTCA procedure is thus often required.
Current therapies for the prevention and treatment of thrombus formation associated with various disease states and surgical procedures have focused primarily on the use of the anticoagulants heparin or warfarin. Most commonly, basic therapy usually involves immediate heparinization which may be followed by long-term administration of warfarin if there is a prolonged risk of thrombus reoccurrence.
Heparin prevents the release of serotonin and thromboxane A.sub.2 from platelets. These vasoactive substances are suspected mediators of the intense pulmonary artery hypertension, acute right-side hemodynamic failure, and cardiogenic shock associated with pulmonary embolism. Heparins' rapid action in preventing thrombus propagation and in blocking platelet release is the rationale for its use. However, a frequent complication of heparinization is major bleeding (usually after 48 hours); such bleeding is especially hazardous if it occurs intracranially. The risk of bleeding is dose related and is higher in woman, in severely ill patients, in individuals who consume large amounts of alcohol, and in individuals who take heparin and aspirin concurrently. Although the action of heparin may be terminated by intravenous injection of protamine sulfate, the use of protamine has been linked to several post-surgical complications, including postoperative systemic hypotension, allergic reactions, catastrophic pulmonary vasoconstriction, acute pulmonary hypertension, complement activation, noncardiogenic pulmonary edema, decreased cardiac output, and thrombocytopenia/leukopenia. Since protamine, usually isolated from fish, can be recognized as a foreign protein by the human immune system, patients with prior protamine exposure (e.g., diabetic patients who have received protamine insulin) are at particular risk during subsequent exposures (Just Viera, Amer. Surgeon 50:151, 1984). Additionally, studies suggest that a non-immunological pathway via complement activation may be responsible for many of the acute reactions observed during protamine reversal of heparin anticoagulation.
Warfarin interferes with the .gamma.-carboxylation of glutamic acid residues in the vitamin K-dependent synthesis of factors II, VII, IX, and X in liver mitochondria. The drug is completely absorbed and is predominantly protein-bound in the plasma, where its half-life is 42 hours. It is degraded in the liver and its metabolites, which are inactive, are excreted in the urine and stool. However, warfarin will not affect procoagulant proteins already formed in the liver and released into the circulation, and the half-life of some of these factors is longer than 24 hours, thus delaying the anticoagulant effects of this drug for several days. In addition, a number of drugs interact significantly with warfarin, and hereditary resistance to warfarin exists as an autosomal dominant trait in some families.
If heparinization is ineffective to stop progression of thrombus formation, or in the cases where occlusion is acute and life threatening, thrombolytic therapy is usually used. Three thrombolytic agents are currently used; urokinase, which is harvested from human fetal kidney cells and cleaves plasminogen to plasmin; streptokinase, which is derived from streptococci and complexes with and activates plasminogen; and recombinant tissue plasminogen activator (rtPA). These agents may hasten thrombus dissolution, but they also lyse hemostatic fibrin and may cause hemorrhaging. Thus, concurrent use of these thrombolytic agents with heparin or warfarin is usually avoided. In addition, the nonrecombinant agents are pyrogens and potential allergens, especially streptokinase, which has been associated with anaphylaxis.
Although venous thrombosis during pregnancy is common, and pulmonary embolism is a leading cause of maternal mortality, anticoagulant therapy during pregnancy poses significant therapeutic problems. Warfarin crosses the placenta and affects the fetus, in addition to being associated with hemorrhagic complications. Embryopathy (nasal hypoplasia, altered bone growth, and stippled epiphyses) has been clearly attributed to coumarin derivatives; the critical period for exposure appears to be between the sixth week and the twelfth week of gestation. Far less common are such serious fetal central nervous system abnormalities as mental retardation, blindness, deafness, spasticity, and seizures. These defects appear to be unrelated to any critical period of exposure and may be associated with warfarin administration during the second and third trimesters. Various congenital ocular abnormalities have also been reported after warfarin therapy.
Heparin does not cross the placenta, and currently, adjusted-dose heparin is the preferred anticoagulant used during pregnancy complicated by venous thromboembolism. However, in one study, about one-eighth of the pregnancies treated with heparin ended in stillbirth, and one fifth of the mothers gave birth to premature infants, one third of whom died. Other problems associated with heparin administration during pregnancy include retained placenta, premature detachment of the placenta and minor hematomas.